Antidepressant-like activity of venlafaxine and clonidine in mice exposed to single prolonged stress - A model of post-traumatic stress disorder. Pharmacodynamic and molecular docking studies

作者：Malikowska Natalia; Fijalkowski Lukasz; Nowaczyk Alicja; Popik Piotr; Salat Kinga^*

来源：Brain Research, 2017, 1673: 1-10.

DOI：10.1016/j.brainres.2017.08.001

• Single prolonged stress model of post-traumatic stress disorder
• Forced swim test
• Clonidine
• Venlafaxine
• Monoamine transporters
• Molecular docking

Background: Post-traumatic stress disorder (PTSD) is a growing issue worldwide characterized by stress and anxiety in response to re-experiencing traumatic events which strongly impair patient's quality of life and social functions. Available antidepressant and anxiolytic drugs are not efficacious in the majority of treated individuals. This necessitates a significant medical demand to develop novel therapeutic strategies for PTSD.
Experimental Approach: Animal model of PTSD was induced using a mouse single prolonged stress protocol (mSPS). To assess the activity of venlafaxine and clonidine, the forced swim test (FST) was used repeatedly 24 h, 3 days, 8 days, 15 days and 25 days after mSPS. To get insight into a possible mechanism of anti-PTSD action, molecular docking procedure was utilized for the most active drug. This in silico part comprised molecular docking of enantiomers of venlafaxine to human transporters for serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT).
Key Results: In mSPS-subjected mice FST revealed the effectiveness of venlafaxine, however in non SPS-subjected mice both venlafaxine and clonidine were active. Molecular docking studies indicated that the affinity of venlafaxine to monoamine transporters is growing in the following rank order: hDAT < hNET < hSERT. Both venlafaxine enantiomers present different selectivity and binding mode.
Conclusion and Implications: Venlafaxine but not clonidine was effective in an animal model of PTSD. Its mechanism of action, i.e., SERT, NET and DAT inhibition indicates potential drug targets for PTSD treatment. We expect that these results will contribute to a broader application of VLX in PTSD patients.

• 出版日期2017-10-15